Effect of peroxisome proliferator-activated receptor γ ligand. Rosiglitazone on left ventricular remodeling in rats with myocardial infarction

Geng, Deng-feng; Wei, Wenxin; Jin, Dongmei; Wang, Jingfeng; Wu, Yan

doi:10.1016/j.ijcard.2006.03.060

Cited by 40 publications

(24 citation statements)

References 33 publications

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“…28 Previous experimental investigations revealed that PPAR-g agonists can improve LV systolic and diastolic function by attenuating unfavorable LV remodeling in animal models of MI. [3][4][5] Telmisartan inhibits Ang II type I receptor (AT1R) not only by direct blockade of AT1R but also by downregulation of AT1R expression through a PPAR-g-mediated pathway, thereby inhibiting the RAAS more completely than other ARBs. 29 Thus, Telmisartan effectively inhibits unfavorable LV remodeling via both AT1R blockade and an anti-inflammatory effect mediated by PPAR-g activation.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well as anti-fibrotic activity by inhibiting transforming growth factor b-1 (TGF-b1) signaling, and the activity of matrix metalloprotease (MMP)-2/9 and the osteopontin (OPN). [6][7][8][9] Telmisartan is a structurally unique ARB that acts as a partial PPAR-g agonist (activating the receptor 25-30% of the maximum level achieved by full PPAR-g agonists) as well as an ARB, 10 thereby improving insulin resistance and lipid metabolism as well as reducing the blood pressure.…”

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confidence: 99%

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Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-g (PPAR-g) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-g agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-g antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor b-1 (TGF-b1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-g and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-g and TIMP-1, and inhibition of TGF-b1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-g activation were suggested to be important in addition to suppression of Ang II activity. Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by hypertrophy associated with interstitial fibrosis of the noninfarcted myocardium, and causes LV dilatation and cardiac dysfunction. It is known that angiotensin II (Ang II) has a crucial role in the development of unfavorable LV remodeling, and recent studies based on animal experiments have demonstrated that treatment with an Ang-converting enzyme inhibitor (ACE-I) and/or Ang II type I receptor blocker (ARB) can attenuate unfavorable LV remodeling. 1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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“…Indeed, renal retention of sodium and cardiac hypertrophy in rats with CHF induced by ACF are highly dependent on the activity of the renin-angiotensin system and may be reversed or prevented by treatment with ACE inhibitors or angiotensin receptor blocker. 27,28 Furthermore, Geng et al 36 demonstrated that RGZ treatment in rats with myocardial infarction inhibited myocardial angiotensin II and aldosterone generation and improved cardiac remodeling. In fact, several studies with TZDs in experimental models of cardiac injury, in particular myocardial ischemic injury in normal rats as well as in diabetic rodent models, demonstrated potential cardiovascular protective actions of these drugs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

Goltsman

Wang

LaVallie

et al. 2011

Circ: Heart Failure

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Background-The side effects of fluid retention and edema of the thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor-␥ agonists limit their use in patients with congestive heart failure (CHF). The present study aims to explore whether chronic treatment with the TZD compound rosiglitazone (RGZ) is associated with worsening of salt and water retention in male Sprague-Dawley rats with aorto-caval fistula, an experimental model of volume-overload CHF. Methods and Results-The effects of oral RGZ (30 mg/kg per day for 4 weeks) in CHF rats on plasma volume, cumulative sodium excretion, renal expression of Na ϩ channels and transporters, and selected biomarkers of CHF were compared with those in CHF rats and sham-operated control rats treated with vehicle only (nϭ7 to 10). Additionally, the response to acute saline loading (3.5% of body weight) was evaluated after 2 weeks of treatment by renal clearance methodology. Chronic RGZ treatment caused no further increase in plasma volume compared with vehicle-treated CHF rats. Moreover, no increase in renal expression of Na ϩ transport-linked channels/transporters was observed in response to RGZ. Cumulative sodium excretion was enhanced in CHF rats after RGZ and by another TZD compound, pioglitazone. In response to saline loading, RGZ-treated animals displayed a higher natriuretic/diuretic response than did vehicle-treated rats. Chronic RGZ treatment was not associated with any deterioration in selected biomarkers of CHF, whereas indices of cardiac hypertrophy and blood pressure were improved. Conclusions-Chronic RGZ treatment was not associated with worsening of fluid retention or cardiac status in rats with experimental volume-overload CHF. Rather, RGZ appeared to improve renal handling of salt and water in rats with CHF. (Circ Heart Fail. 2011;4:345-354.)Key Words: thiazolidinedione Ⅲ aorto-caval fistula Ⅲ renal sodium excretion Ⅲ ECF volume expansion Ⅲ rat R osiglitazone (RGZ) is a member of the thiazolidinedione (TZD) class of compounds that act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-␥). 1 Activation of PPAR-␥ exerts important metabolic effects by regulating the expression of genes involved in glucose and lipid metabolism. 2 Oral RGZ is highly effective in improving insulin sensitivity and the metabolic abnormalities of type 2 diabetes mellitus (T2DM). 1 However, the clinical benefits of TZDs are hampered by the concomitant adverse effects of fluid retention and peripheral edema. These were reported in 4% to 7% of TZD-treated patients and in up to 15% in those who receive concurrent insulin therapy. [3][4][5] Moreover, the overall cardiovascular safety of these drugs has been questioned on the basis of observations of increased incidence of heart failure and cardiac ischemic events in RGZ-treated patients. 6 -8 In particular, the increase in cardiac events led recently to more restrictive measures on RGZ use in patients with T2DM. 9,10 Indeed, the original guidelines of the American Heart Association (AHA) prohibit th...

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“…21 Several other studies have demonstrated that TZDs attenuate ischemia/reperfusion injury to the myocardium, intestine, kidney, and lung. [22][23][24][25] Another activator of PPAR␥ is connecting peptide (C-peptide). C-peptide is a 31-amino acid peptide cleaved from proinsulin during the insulin biosynthesis.…”

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confidence: 99%

Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice

et al. 2008

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The function of peroxisome proliferator-activated receptor-␥ (PPAR␥) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPAR␥ in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPAR␥ was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPAR␥ activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPAR␥, retinoid X receptor-␣ (RXR␣), and PPAR␥/RXR␣ heterodimer expression was maintained. Accompanying the decrease in PPAR␥ activation was a decrease in the expression of the natural ligand 15-deoxy-Delta 12,14 -prostaglandin J 2 . This was associated with reduced interaction of PPAR␥ and the coactivator, p300. To determine whether PPAR␥ activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPAR␥ agonists, rosiglitazone and connecting peptide. These treatments increased PPAR␥ activation and reduced liver injury compared to untreated mice. Furthermore, PPAR␥-deficient mice had more liver injury after ischemia/reperfusion than their wildtype counterparts. Conclusion: These data suggest that PPAR␥ is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury. I schemia and reperfusion of the liver is a primary complication of liver resection surgery, transplantation, and trauma. 1 This insult can lead to hepatocellular damage and organ dysfunction through the initiation of a biphasic inflammatory response. 2 The initial phase of this response is characterized by activation of Kupffer cells and their subsequent production and release of reactive oxygen species. This causes mild injury to the hepatic parenchyma, but the oxidative stress activates redox-sensitive transcription factors, such as nuclear factor B and activator protein-1, that regulate the expression of many proinflammatory mediators. [3][4][5] Proximal cytokines, such as interleukin-12 (IL-12), tumor necrosis factor-␣ (TNF␣), and IL-1 are critically involved in promoting the second phase of liver injury by inducing the hepatic expression of neutrophil-attracting CXC chemokines and endothelial cell adhesion molecules. 6-11 CD4 T lymphocytes are also recruited to the liver early during reperfusion, and these cells facilitate the subsequent recruitment of neutrophils by modulating chemokine expression. 12,13 The cooperative effects of CXC chemokines and adhesion molecules result in adherence of neutrophils in the hepatic microcirculation and their subsequent transmigration into the hepatic parenchyma. Accumulated neutrophils release oxidants and proteases that directly injure hepatocytes and vascular endothelial cells. 14

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Effect of peroxisome proliferator-activated receptor γ ligand. Rosiglitazone on left ventricular remodeling in rats with myocardial infarction

Cited by 40 publications

References 33 publications

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice

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